Lungs Of Offspring Research Articles

Vitamin C Supplementation for Pregnant Smoking Women and Pulmonary Function in Their Newborn Infants

Importance Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function. Objective To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo. Design, Setting, and Participants Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year. Interventions Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). Main Outcomes and Measures The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed. Results Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H 2 O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) ( P Conclusions and Relevance Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities. Trial Registration clinicaltrials.gov Identifier:NCT00632476

Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial.

Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function. To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo. Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year. Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed. Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P < .001 for interaction). Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities. clinicaltrials.gov Identifier: NCT00632476.

Metyrapone Blocks Maternal Food Restriction-Induced Changes in Female Rat Offspring Lung Development

Maternal food restriction (MFR) during pregnancy affects pulmonary surfactant production in the intrauterine growth-restricted (IUGR) offspring through unknown mechanisms. Since pulmonary surfactant production is regulated by maternal and fetal corticosteroid levels, both known to be increased in IUGR pregnancies, we hypothesized that metyrapone (MTP), a glucocorticoid synthesis inhibitor, would block the effects of MFR on surfactant production in the offspring. Three groups of pregnant rat dams were used (1) control dams fed ad libitum; (2) MFR (50% reduction in calories) from days 10 to 22 of gestation; and (3) MFR + MTP in drinking water (0.5 mg/mL), days 11 to 22 of gestation. At 5 months, the MFR offspring weighed significantly more, had reduced alveolar number, increased septal thickness, and decreased surfactant protein and phospholipid synthesis. These MFR-induced effects were normalized by the antiglucocorticoid MTP, suggesting that the stress of MFR causes hypercorticoidism, altering lung structure and function in adulthood.

Maternal 25‐hydroxyvitamin D and its association with childhood atopic outcomes and lung function

BackgroundIt has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed.ObjectiveTo examine the association between blood total maternal 25-hydroxy vitamin D (25(OH)D) concentrations in pregnancy and offspring asthma, atopy and lung function in the largest birth cohort study to date.MethodsParticipants were largely of white European origin and resident in the South West of England. We examined the associations of maternal 25(OH)D concentrations in pregnancy with the following outcomes in the offspring: wheeze, asthma, atopy, eczema, hayfever, at mean age 7.5 years (n = 3652–4696 depending on outcome), IgE at 7 years (n = 2915) and lung function and bronchial responsiveness at mean age 8.7 years (n = 3728–3784).ResultsSixty-eight per cent of mothers had sufficient (> 50 nmol/L) concentrations of 25(OH)D, 27% were insufficient (27.5–49.99 nmol/L) and 5% were deficient (< 27.5 nmol/L). There was no evidence to suggest that maternal 25(OH)D concentration in pregnancy was associated with any respiratory or atopic outcome in the offspring. These findings remained after adjustment for season of measurement and for potential confounders. There was also no evidence that these relationships followed a non-linear form and no evidence that either deficient or high concentrations of maternal 25(OH)D were associated with atopic or respiratory outcomes.ConclusionsWe found no evidence that maternal blood 25(OH)D concentration in pregnancy is associated with childhood atopic or respiratory outcomes.

The effect of maternal exposure to di-(2-ethylhexyl)-phthalate on the lung of albino rat offspring

Introduction Di-(2-ethylhexyl)-phthalate (DEHP) is present in a wide variety of medical devices. Infants are more susceptible than the general population. Aim of work To investigate histological and immnohistochemical changes in the lung of newborn rats in response to mothers’ exposure. Materials and methods Twenty nonpregnant adult female albino rats were used. After pregnancy, on the 15th day of pregnancy, dams were divided into two equal groups: the control group received corn oil and the treated group received DEHP (500 mg/kg/day) from the 15th day of pregnancy and during the 1st three weeks of lactation. Fifteen offspring from each group were subdivided into three subgroups, 1, 2, and 3, which were sacrificed at the 2nd, 7th, and 21st postnatal day, respectively. Lung specimens were processed for light microscope (H&E and immunohistochemical staining of proliferating cell nuclear antigen) and electron microscope examination. Results H&E-stained sections of treated lung on the 2nd day showed variable-sized saccules. Primary septa were significantly thicker than those of the control group. However, on the 7th day, focally dilated saccules with thin primary septa were observed. Saccules and secondary septa were fewer than those in the control group. On the 21st day, variable-sized alveoli and a significant increase in septal thickness were observed. Immunohistochemically, there was a significant increase in proliferating cell nuclear antigen-positive cells on both the 2nd day and the 21st day, whereas they decreased on the 7th day in comparison with the control group. Ultrastructurally, treated lung on the 2nd day showed a saccular wall with many layers of interstitial cells, some with shrunken nuclei, whereas on the 7th day, thin septa were observed. Type II pneumocytes and interstitial cells had heterochromatic shrunken nuclei, whereas on the 21st day, the presence of macrophages was observed in the lumen. Interstitials cells and type II pneumocytes showed heterochromatic nuclei and marked distortion of organelles. Conclusion DEHP induced marked histological and immunohistochemical changes in the lung. Alternative plasticizers with less adverse impact could be used. Further studies on the possible protective effect of antioxidants are recommended.

Intrauterine exposure to flavonoids modifies antioxidant status at adulthood and decreases oxidative stress-induced DNA damage

Maternal intake of flavonoids, known for their antioxidant properties, may affect the offspring's susceptibility to developing chronic diseases at adult age, especially those related to oxidative stress, via developmental programming. Therefore, we supplemented female mice with the flavonoids genistein and quercetin during gestation, to study their effect on the antioxidant capacity of lung and liver of adult offspring. Maternal intake of quercetin increased the expression of Nrf2 and Sod2 in fetal liver at gestational day 14.5. At adult age, in utero exposure to both flavonoids resulted in the increased expression of several enzymatic antioxidant genes, which was more pronounced in the liver than in the adult lung. Moreover, prenatal genistein exposure induced the nonenzymatic antioxidant capacity in the adult lung, partly by increasing glutathione levels. Prenatal exposure to both flavonoids resulted in significantly lower levels of oxidative stress-induced DNA damage in liver only. Our observations lead to the hypothesis that a preemptive trigger of the antioxidant defense system in utero had a persistent effect on antioxidant capacity and as a result decreased oxidative stress-induced DNA damage in the liver.

Sex-Specific Perinatal Nicotine-Induced Asthma in Rat Offspring

Recently, we have suggested that down-regulation of homeostatic mesenchymal peroxisome proliferator-activated receptor γ signaling after in utero nicotine exposure might contribute to asthma. Here, we have exploited an in vivo rat model of asthma to determine if the effects of perinatal nicotine exposure on offspring pulmonary function and mesenchymal markers of airway contractility in both tracheal and lung parenchymal tissue are sex specific, and whether the protection afforded by the peroxisome proliferator-activated receptor γ agonist, rosiglitazone (RGZ), against the perinatal nicotine-induced effect on offspring lung is also sex specific. Pregnant rat dams received placebo, nicotine, or nicotine plus RGZ daily from Embryonic Day 6 until Postnatal Day 21, at which time lung resistance, compliance, tracheal contractility, and the expression of structural and functional mesenchymal markers of pulmonary contractility were determined. Compared with control animals, perinatal nicotine exposure caused a significant increase in airway resistance and a decrease in airway compliance after a methacholine challenge in both male and female offspring, with more pronounced changes in the males. In contrast to this, the effects of perinatal nicotine exposure on acetylcholine-induced tracheal constriction, along with the expression of its mesenchymal markers, were observed exclusively in the male offspring. Concomitant treatment with RGZ normalized the nicotine-induced alterations in pulmonary function in both sexes, as well as the male-specific effects on acetylcholine-induced tracheal constriction, along with the affected mesenchymal markers. These data suggest that perinatal nicotine exposure causes sex-specific perinatal cigarette smoke exposure-induced asthma, providing a powerful phenotypic model for unequivocally determining the underlying nature of the cell molecular mechanism for this disease.

Maternal nicotine exposure-induced collagen pulmonary changes

Nicotine is an alkaloid by high level of addictive property that can quickly assimilate from smoker’s lung. It passes from the placenta and gathers in the developing fetus. Our previous study showed that collagen type IV plays a critical role in basement membrane of different embryonic organs. In this study the effect of maternal nicotine was evaluated by collagen IV changes in lung of mice offspring during pre and postnatal period. Pregnant Balb/C mice were divided into 2 experimental and 2 control groups. Experimental group 1 received 3 mg/kg nicotine intrapritoneally from day 5 of gestation to last day of pregnancy. Experimental group 2 received the same amount of nicotine during the same gestational days as well as 2 first week after birth. The control groups received the same volume of normal saline during the same periods. At the end of exposure times, all newborns were anesthetized and their lungs were removed and immunohistochemical study for tracing collagen was carried out. Our results showed that collagen reaction in the bronchial basement membrane (BBM) and extra cellular matrix (ECM) of the lung parenchyma experienced a remarkable increase when compared to the control ones. Cell necrosis definition in lung parenchyma of the experimental group 2 was the other finding that our investigation revealed. These data indicate that maternal nicotine exposure may induce a noticeable collagen increase with a reasonable amount in BBM and ECM of respiratory system of next generation.

Developmental nicotine exposure results in programming of alveolar simplification and interstitial pulmonary fibrosis in adult male rats

AimsTo determine the long-term effect of maternal nicotine intake on the lung development of the offspring in adult life, we analyzed the alveolar structure, protein expression in the adult rat offspring lungs. MethodsWe determined animal body weight (BW), lung weight (LW), lung/body weight ratio (L/BWR), lung volume (LV), radial alveolar count (RAC), alveolar septal thickness (AST) and expression of collagen, AT1R, AT2R, TGF-β1, pSmad3, Smad3 and CTGF proteins. ResultsMale offspring lung showed decreased RAC, thickened alveolar septa, increased collagen, AT1R, TGF-β1, pSmad3 and CTGF proteins. In contrast, female offspring lungs had reduced L/BWR, increased LV, and expression of AT2R, resulting in decreased AT1R to AT2R ratio. ConclusionsMaternal nicotine use during development programs abnormal lung development in male rats. This finding links maternal nicotine use to increased susceptibility to interstitial pulmonary fibrosis in adult male but not female offspring, indicating sex-dependent effects of developmental nicotine exposure.

Antenatal nicotine exposure results in programming of aberrant alveolar development and interstitial pulmonary fibrosis in adult male rats

ObjectiveIdentification of abnormalities in lung structure, and expression of profibrotic proteins in the adult rat offspring lung exposed to maternal smoking in fetal life.MethodsAntenatal nicotine exposed adult offspring lungs were analyzed for lung volume (LV), lung/body weight ratio (L/BWR), morphology, and protein expression patterns.ResultsMale offspring lung showed decreased radial alveolar count, thickened alveolar septa, with heightened interstitial collagen expression, angiotensin II type 1 receptor (AT1R), TGF‐ β1, and CTGF proteins. In contrast, female offspring lungs had reduced L/BWR, increased LV, and expression of angiotensin II type 2 receptor (AT2R), resulting in the decreased AT1R to AT2R ratio. Smad3 expression was down‐regulated in male but not in female lungs.ConclusionsAntenatal nicotine exposure results in fetal programming of abnormal lung development linking maternal nicotine use to increased susceptibility of interstitial pulmonary fibrosis in adult male offspring lung in a sex‐dependent manner.Supported in part by NIH grant HL83966

Maternal DHA Supplementation Improves Lung Growth and Function in Offspring Exposed to LPS and Hyperoxia

BackgroundMaternal inflammation contributes to low birth weight and preterm delivery. Premature infants routinely receive therapeutic oxygen and exhibit persistently diminished respiratory function into adulthood.ObjectiveWe tested the hypothesis that DHA supplementation reduces the detrimental effects of a hostile perinatal environment.MethodsPregnant C3H/HeN mice were fed DHA or control diet (CD) and injected with LPS or saline on embryonic day (E) 16. Offspring were placed in room air (RA) or 85% O2 for 14 d then returned to RA. PFTs, microCTs, molecular, and histological analyses were performed.Main ResultsBirth weight was reduced in pups born to CD/LPS dams but not different than controls in the pups born to DHA/LPS dams. At 8 weeks of age, bodyweights were lower, the lungs had fewer and larger alveoli, and static compliance was decreased in mice born to dams fed CD and exposed to LPS/O2. Maternal dietary supplementation with DHA in LPS/O2 exposed mice reversed these effects even at 8 weeks with bodyweights, alveolarization, and PFT measurements in not different than CD or DHA diet, saline injected, RA exposed controls.ConclusionsThe detrimental effects of systemic maternal inflammation and neonatal hyperoxia exposure on offspring lung structure and function in adulthood can be reduced by maternal DHA supplementation.

Effects of maternal food restriction on offspring lung extracellular matrix deposition and long term pulmonary function in an experimental rat model

Intrauterine growth restriction (IUGR) increases the risk of respiratory compromise throughout postnatal life. However, the molecular mechanism(s) underlying the respiratory compromise in offspring following IUGR is not known. We hypothesized that IUGR following maternal food restriction (MFR) would affect extracellular matrix deposition in the lung, explaining the long-term impairment in pulmonary function in the IUGR offspring. Using a well-established rat model of MFR during gestation to produce IUGR pups, we found that at postnatal day 21, and at 9 months (9M) of age the expression and abundance of elastin and alpha smooth muscle actin (αSMA), two key extracellular matrix proteins, were increased in IUGR lungs when compared to controls (P < 0.05, n = 6), as determined by both Western and immunohistochemistry analyses. Compared to controls, the MFR group showed no significant change in pulmonary resistance at baseline, but did have significantly decreased pulmonary compliance at 9M (P < 0.05 vs. control, n = 5). In addition, MFR lungs exhibited increased responsiveness to methacholine challenge. Furthermore, exposing cultured fetal rat lung fibroblasts to serum deprivation increased the expression of elastin and elastin-related genes, which was blocked by serum albumin supplementation, suggesting protein deficiency as the predominant mechanism for increased pulmonary elastin deposition in IUGR lungs. We conclude that accompanying the changes in lung function, consistent with bronchial hyperresponsiveness, expression of the key alveolar extracellular matrix proteins elastin and αSMA increased in the IUGR lung, thus providing a potential explanation for the compromised lung function in IUGR offspring.

Intrauterine Growth Restriction‐Associated Increase in Lung Elastin is Due to Protein Deficiency

ObjectivesTo determine 1) if increased lung elastin in intrauterine growth restricted (IUGR) infant is due to altered alveolar interstitial fibroblast (AIF) differentiation and 2) the specific nutrient deficiency that leads to increased elastin gene expression in the IUGR infant lung.MethodsPregnant rat dams were fed ad lib or on 50% food‐restricted diet. The pups were killed at 9 months and lungs were examined for elastin gene expression (RT‐PCR and Western blotting). Primary rat lung fibroblasts were cultured in DMEM ± fetal bovine serum (FBS), Vitamin D (VD), arachidonic acid (ARA) +doxohexanoic acid (DHA), or bovine serum albumin (BSA)‐ then the expression of elastin and activation of mTOR signaling were examined.ResultsWith food restriction there was a significant increase in elastin gene expression. Culturing primary AIFs without FBS significantly increased the expression and protein levels of various elastin‐related genes, accompanied by mTOR activation. FBS‐restriction associated increase in elastin expression and mTOR activation were only partially blocked by VD and ARA+DHA, but completely blocked with BSA.ConclusionsElastin expression is significantly increased in the lungs of IUGR offspring; this increase is largely due to protein deficiency; and AIF mTOR signaling plays an important role in increased elastin levels in the IUGR offspring lung. (Grant: NIH (HD‐58948).

Prenatal PFOS exposure induces oxidative stress and apoptosis in the lung of rat off-spring

Perfluorooctane sulfonate (PFOS) could induce neonatal pulmonary injuries in rodents. The aim of this study was to investigate the underlying mode of action. Pregnant rats were dosed orally with PFOS (0, 0.1 and 2.0mg/kgd) from gestation days (GD) 1 to 21. Lung samples from postnatal day (PND) 0 and 21 pups were analyzed for the toxic effects of PFOS. The results showed that maternal exposure to 2.0mg/kgd PFOS caused severe histopathological changes along with marked oxidative injuries and cell apoptosis in offspring lungs; at the same time, the ratio of Bax to Bcl-2, release of cytochrome c (Cyt c) from mitochondria to cytoplasm, expressions of Fas and Fas-L, and activities of caspase-3, -8 and -9 were up-regulated correspondingly. The results indicate that oxidative stress and both intrinsic and extrinsic cell death pathways were involved in prenatal PFOS exposure-induced injuries in postnatal lungs.

PPARγ agonist rosiglitazone prevents perinatal nicotine exposure-induced asthma in rat offspring

Perinatal exposure to maternal smoke is associated with adverse pulmonary effects, including reduced lung function and increased incidence of asthma. However, the mechanisms underlying these effects are unknown, and there is no effective preventive and/or therapeutic intervention. Recently, we suggested that downregulation of homeostatic mesenchymal peroxisome proliferator-activated receptor-γ (PPARγ) signaling following in utero nicotine exposure might contribute to chronic lung diseases such as asthma. We used an in vivo rat model to determine the effect of perinatal nicotine exposure on 1) offspring pulmonary function, 2) mesenchymal markers of airway contractility in trachea and lung tissue, and 3) whether administration of a PPARγ agonist, rosiglitazone (RGZ), blocks the molecular and functional effects of perinatal nicotine exposure on offspring lung. Pregnant Sprague-Dawley rat dams received placebo, nicotine, or nicotine + RGZ daily from embryonic day 6 until postnatal day 21, when respiratory system resistance, compliance, tracheal contractility, and the expression of markers of pulmonary contractility were determined. A significant increase in resistance and a decrease in compliance under basal conditions, with more pronounced changes following methacholine challenge, were observed with perinatal nicotine exposure compared with control. Tracheal constriction response and expression of mesenchymal markers of airway contractility were also significantly increased following perinatal nicotine exposure. Concomitant treatment with RGZ completely blocked the nicotine-induced alterations in pulmonary function, as well as the markers of airway contractility, at proximal and distal airway levels. These data suggest that perinatal smoke exposure-induced asthma can be effectively blocked by PPARγ agonists.

Abstract 184: Stress-induced father-mediated 45S rRNA genetic and epigenetic reprogramming

Abstract Environmental and dietary factors modify genomes and phenotypes. The extents of these modifications are not clear. DNA methylation and genotypes of the multi-copy 45S rRNA gene were quantified in 4 tissues at 3 developmental stages (sperm of 128 treated males, 98 litters of 876 day-8 embryos, and lung, liver, and a subset of sperm from 93 litters of 758 6-week adult offspring) in 3 treatment groups. Mixed models for adjusting confounding factors were used for all statistical analyses. Single injections of 1 mmol/kg chromium(III), [Cr(III)], an environmental agent and a dietary supplement, or acid saline (AS) vehicle were given to male mice only, which were then euthanized or bred 2 weeks later. A trend toward hypomethylation in the rRNA spacer promoter region but no frequency differences in 5 sequence variants of the rRNA, defined by 4 single nucleotide polymorphisms, were observed in sperm 2 weeks after Cr(III) treatment as compared to AS and untreated (UT) groups. This epigenetic trend disappeared at the day-8 embryo stage for both genders after paternal treatments with Cr(III) and/or AS. In offspring at 6 weeks of age, significant hypermethylation of the rRNA spacer-promoter was detected in the lung of the male offspring from Cr(III)-treated fathers, reversing the hypomethylation trend seen in the sperm 2 weeks after Cr(III) treatment. There was also a change in genotype: a significant reduction of the rRNA CGC variant in Cr(III) and/or AS groups in lung and liver in males, and in lung in females. Further examinations of the regressions of individual sequence variants on DNA methylation and on other variants revealed significant modifications to those correlates by Cr(III) and/or AS but to different degrees depending on the developmental stages, thus supporting the hypothesis of paternal exposure-induced epigenetic and genetic reprogramming. These genomic reprogrammings were accompanied by phenotypic changes related to paternal Cr(III) or AS treatment, including increased body and liver weights and alterations in serum glucose and leptin. Male mice treated with either Cr(III) or AS demonstrated a typical chemical stress response, as indicated by acute reduction in serum insulin and leptin, followed later by increases in these hormones. Taken together, this multi-faceted cross-generational study uncovers modifiable epigenetic and genetic reprogramming during development and differentiation. Paternal stress apparently had multiple effects on genomes and phenotypes, in their offspring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 184.

Perinatal Nicotine Exposure‐Induced Upper Airway and Lung Parenchymal Structural and Functional Changes are Blocked by Concomitant PPARγ Agonist Administration

Recently, we have demonstrated the down‐regulation of the homeostatic alveolar mesenchymal PPARγ signaling and the up‐regulation of Wnt signaling in offspring lung following perinatal exposure to nicotine (NC). However, the molecular and functional alterations in upper airways in this setting are not known. Our objectives were to determine the effects of a PPARγ agonist on perinatal nicotine exposure‐induced alterations in 1) mesenchymal markers of tracheal constriction, and 2) acetylcholine‐induced tracheal constriction responses. Pair‐fed pregnant Sprague Dawley rat dams received diluent, NC (1 mg/kg, sc), and NC (1 mg/kg, sc) + a PPARγ agonist, Rosiglitazone (RGZ) (3 mg/kg, i.p), once daily from e6 until the pups were 21‐days old, when the pups were sacrificed and tracheas collected for mRNA/protein expression and tracheal tension studies. Compared to control, with perinatal NC exposure, mRNA and protein expression of α‐smooth muscle actin, calponin, collagen 1 and 3 were significantly increased. Similarly, compared to controls, tracheal constriction responses were also significantly increased. Concomitant treatment with RGZ blocked the NC‐induced alterations in both tracheal constriction marker expression and constriction responses. Alterations in upper airway function in a rodent model of perinatal NC exposure were blocked by concomitant administration of RGZ. We speculate that perinatal smoke exposure‐induced asthma in offspring can be effectively prevented by PPARγ agonists. Disclosure: Supported by grants from the NIH (HL75405, HD51857, HD058948) and the TRDRP (14RT‐0073, 15IT‐0250, 17RT‐0170).

The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study

Objectives To obtain valid estimates of the association between body mass index (BMI) and mortality by using offspring BMI as an instrumental variable for own BMI.Design Cohort study based on...

Effects of decabrominated diphenyl ether (DBDE) on developmental immunotoxicity in offspring mice

Decabrominated diphenyl ether (DBDE), a representative brominated flame retardant ubiquitous in the environment, is suspected of being hazardous to humans. We evaluated the developmental immunotoxicity of DBDE by an assay system using respiratory syncytial virus (RSV) infection in offspring mice. Pregnant mice were continuously exposed to DBDE (10, 100, 1000, or 10,000 ppm) in the diet from gestation day 10 to weaning on postnatal day 21. Offspring mice born to these dams were intranasally infected with RSV. Virus titers in the lungs of RSV-infected offspring exposed perinatally to DBDE increased dose-dependently compared with the control. The level of interferon-γ in the bronchoalveolar lavage fluids and gene expression of the chemokine RANTES in the lungs were also significantly elevated in offspring mice exposed to DBDE. Histopathological analysis revealed that pneumonia in the lungs of offspring mice exposed to 10,000 ppm of DBDE was exacerbated compared with the control. These results indicate that DBDE is a developmental immunotoxic agent.

Effects of dexamethasone on lung morphogenesis in rats and the expression of Wnt signal transduction pathway in the lung of offspring

Multiple signal transduction pathways, for example, Wnt signal transduction pathway, fibroblast growth factor (FGF), bone morphogenetic protein (BMP) etc, are involved in rat fetal lung development. Wnt signal has been shown to play important roles in regulating cell differentiation and proliferation. It is demonstrated that antenatal dexamethasone (DEX) use can induce lung dysplasia. A rat premature delivery model was developed in this study to compare the effects of DEX on antenatal rat fetal lung morphogenesis and the expressions of Wnt7b, beta-catenin and glycogen synthase kinase 3beta (GSK-3beta) genes in the lung of offspring on 19th day of embryo. Twelve pregnant rats were divided into three groups randomly: small dose DEX group, large dose DEX group and control group with 4 rats in each group. The rats in the control group were injected with saline 0.5 ml/d; those in small dose DEX group were injected with DEX 0.4 mg/(kg.d), the rats in large dose DEX group were injected with DEX 0.8 mg/(kg.d), DEX was diluted to 0.5 ml by saline. On the 19th day of gestation, the fetuses were surgically taken out and the histologic structures of fetal rat lungs were observed with light microscope. The RT-PCR and Western-blot methods were used to detect the expressions of Wnt7b, GSK-3beta and beta-catenin genes mRNA and protein. (1) Changes of histologic structure included alveolar numbers: small dose DEX group (15.6 +/- 2.1), large dose DEX group (13.2 +/- 1.6), control group (20.8 +/- 2.0); thickness of alveolar septum: small dose DEX group (11 +/- 5) microm, large dose DEX group (11 +/- 4) microm, control group (13 +/- 7) microm; alveolar space: small dose DEX group (2483 +/- 1336) microm2, large dose DEX group (2924 +/- 1705) microm(2), and control group (1913 +/- 764) microm(2). All the parameters showed significant difference between DEX groups and control group. (P < 0.01 for all comparisons). (2) The expressions of Wnt7b (0.55 +/- 0.19, 0.64 +/- 0.54) and beta-catenin (2.03 +/- 0.58, 2.40 +/- 0.89) genes mRNA of the study groups were significantly higher as compared with those of the control group [Wnt7b (0.18 +/- 0.10), beta-catenin (1.77 +/- 0.54)] (P < 0. 05 for all comparisons) while the expressions of GSK-3beta (1.0 +/- 0.5) were lower than those of the control group (1.1 +/- 0.6) (P < 0. 05). The expressions of GSK-3beta protein in cytoplasm of the study groups [(26.6 +/- 19.7) microg, (10.7 +/- 7.4)microg] reduced gradually while beta-catenin's [(79.5 +/- 1.2) microg, (148.3 +/- 30.4) microg] in the nucleus enhanced simultaneously compared with the control group [(50.0 +/- 00.0) microg ]. Small dose of antenatal DEX usage can improve the fetal lung development, larger dose of DEX may have negative effect on rat fetal lung morphogenesis. Antenatal DEX usage can change the expressions of Wnt7b, GSK-3beta and beta-catenin genes mRNA and protein, these changes may result in paramorphia during pregnancy.